Immunotherapy, or the use of antibodies for therapeutic purposes has been used in recent years to treat cancer. Passive immunotherapy involves the use of monoclonal antibodies in cancer treatments. See for example, Cancer: Principles and Practice of Oncology, 6th Edition (2001) Chapt. 20 pp. 495-508. These antibodies can have inherent therapeutic biological activity both by direct inhibition of tumor cell growth or survival and by their ability to recruit the natural cell killing activity of the body's immune system. These agents can be administered alone or in conjunction with radiation or chemotherapeutic agents. Rituxan® and Herceptin®, approved for treatment of lymphoma and breast cancer, respectively, are two examples of such therapeutics. Alternatively, antibodies can be used to make antibody conjugates where the antibody is linked to a toxic agent and directs that agent to the tumor by specifically binding to the tumor. Mylotarg® is an example of an approved antibody conjugate used for the treatment of leukemia. Monoclonal antibodies that bind to cancer cells and have potential uses for diagnosis and therapy have been disclosed in publications. See, for example, the following patent applications which disclose, inter alia, some molecular weights of target proteins: U.S. Pat. No. 6,054,561 (200 KD c-erbB-2 (Her2), and other unknown antigens 40-200 KD in size) and U.S. Pat. No. 5,656,444 (50 KD and 55 KD, oncofetal protein). Example of antibodies in clinical trials and/or approved for treatment of solid tumors include: Herceptin® (antigen: 180 kD, HER2/neu), Panorex® (antigen: 40-50 kD, Ep-CAM), HMFG1 (antigen>200 kD, HMW Mucin), C225 (antigens: 150 kD and 170 kD, EGF receptor), Campath® (antigen: 21-28 kD, CD52), and Rituxan® (antigen: 35 kD, CD20).
Another type of immunotherapy is active immunotherapy, or vaccination, wherein the antigen present on a specific cancer evokes the immune response in the patient, i.e., to induce the patient to actively produce antibodies against their own cancer. Active immunization has not been used as often as passive immunotherapy or immunotoxins.
An ideal diagnostic and/or therapeutic antibody would be specific for an antigen present on a large number of cancers, but absent or present only at low levels on any adult tissue. The discovery, characterization, and isolation of a novel antigen which is specifically associated with cancer(s) would be useful in many ways. First, the antigen could be used to make monoclonal antibodies against the antigen. An antibody would ideally have biological activity against cancer cells and be able to recruit the immune system's response to foreign antigens. An antibody could be administered as a therapeutic alone or in combination with current treatments or used to prepare immunoconjugates linked to toxic agents. An antibody with the same specificity but without biological activity when administered alone could also be useful in that an antibody could be used to prepare an immunoconjugate with a radio-isotope, a toxin, or a chemotherapeutic agent or liposome containing a chemotherapeutic agent, with the conjugated form being biologically active by virtue of the antibody directing the toxin to the antigen-containing cells.
One aspect required for the ideal diagnostic and/or therapeutic antibody is the discovery and characterization of an antigen which is associated with a variety of cancers. There are few antigens that are expressed on a number of types of cancer (e.g., “pan-cancer” antigen) that have limited expression on non-cancerous cells. The isolation and purification of such an antigen would be useful for making antibodies (e.g., diagnostic or therapeutic) targeting the antigen. An antibody binding to the “pan-cancer” antigen could be able to target a variety of cancers found in different tissues in contrast to an antibody against an antigen associated with only one specific type of cancer. The antigen would also be useful for drug discovery (e.g., small molecules) and for further characterization of cellular regulation, growth, and differentiation.
Antibodies to CD46 (also known as membrane cofactor protein or MCP), have been reported. See, for example, Sparrow et al. Hum. Immunol. 7:1 (1983); Hsi et. al. Am. J. Reprod. Immunol. Microbiol. 18:21 (1988); Cho et al. Clin. Exp. Immunol. 83:257 (1991); Seya et al. J. Immunol. 145:238 (1990). The expression of CD46 has been reported in certain types of cancer, such as breast cancer (Thorseinsson et al. APMIS 106:869-78 (1998); Hofman et al. Breast Cancer Res. Treat. 32:213-9 (1994)); colon/colorectal cancer (Andrew et al. Cancer Res. 50: 5225-30 (1990); Koretz et al. Br. J. Cancer 68:926-31 (1993); Juhl et al. J. Surg. Oncol. 64:222-30 (1997); Bjorge et al. Cancer Immunol. Immunother. 42:185-92 (1996)); lung cancer (Varsano et al. Clin. Exp. Immunol. 113:173-82 (1998); Varsano et al. Am. J. Respir. Cell. Mol. Biol. 19:522-9 (1998)); ovarian cancer (Bjorge et al. Int. J. Cancer 70:14-25 (1997)); renal cancer (Blok et al. Lab. Invest. 80:335-44 (2000); Gorter et al. Lab. Invest. 74:1039-49 (1996)); pancreatic cancer (Juhl et al. J. Surg. Oncol. 64:222-30 (1997)); and prostate cancer (Jarvis et al. J. Allergy Clin. Immunol 99(NO.1, PART 2): S215 (1997); Liu et al. Cancer Res. 60: 3429-3434 (2000)); see also, PCT WO 02/18948; PCT WO 01/88537.
All references, publications, and patent applications disclosed herein are hereby incorporated by reference in their entirety.